Neutral guests complexation with calix[4]arenes preorganised by intramolecular McMurry reaction

Article abstract of DOI:10.1016/S0040-4039(03)00994-8

The introduction of two aromatic aldehyde moieties into the lower rim of calix[4]arenes led to the precursors that were intramolecularly bridged in the presence of low-valent titanium agents (the McMurry reaction). These compounds, preorganised in the cone conformation, represent novel receptors with good complexation ability towards suitable neutral guest molecules both in solution and in the solid state. The influence of preorganisation and overall rigidity of receptor to the complexation process has been studied.

Full text of DOI:10.1016/S0040-4039(03)00994-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4519–4522
Neutral guests complexation with calix[4]arenes preorganised by
intramolecular McMurry reaction
Pavel Lhota´k,a,* Roman Zieba,a Vit Hroma´dko,a Ivan Stibora,* and Jan Sykorab
aDepartment of Organic Chemistry, Institute of Chemical Technology, Technicka´ 5, 166 28 Prague 6, Czech Republic
bInstitute of Chemical Process Fundamentals, ASCR, Rozvojova 135, 165 02 Prague 6, Czech Republic
Received 12 March 2003; revised 11 April 2003; accepted 17 April 2003
Abstract—The introduction of two aromatic aldehyde moieties into the lower rim of calix[4]arenes led to the precursors that were
intramolecularly bridged in the presence of low-valent titanium agents (the McMurry reaction). These compounds, preorganised
in the cone conformation, represent novel receptors with good complexation ability towards suitable neutral guest molecules both
in solution and in the solid state. The influence of preorganisation and overall rigidity of receptor to the complexation process has
been studied. © 2003 Elsevier Science Ltd. All rights reserved.
Cyclic oligomers of p-substituted phenols and formal-
dehyde, known as calix[n]arenes,1 have found many
applications in supramolecular chemistry2 due to their
simple one-pot preparation and their unique structural
properties. The easily tuneable shape of the molecule,
together with almost unlimited possibilities of chemical
transformation, make calix[n]arenes useful building
blocks in the construction of more sophisticated molec-
ular systems. Calix[4]arene 1 especially is widely used as
a molecular scaffold for the design and synthesis of a
wide range of receptors with recognition ability towards
both neutral and charged molecules.3
a receptor is rather restricted by the small size of the
inner cavity. In this paper we report a simple strategy
leading to receptors with preorganised cavities based on
the McMurry reaction of suitable formyl-substituted7
calix[4]arene derivatives.
Starting tert-butylcalix[4]arene 1 was diametrically
dialkylated with p-cyanobenzyl bromide in refluxing
acetone using K2CO3 as a base to yield derivative 3 in
58% yield (Scheme 1). The cyano groups were then
reduced to aldehydes using DIBAL in chlorobenzene in
81% yield. Unfortunately, p-cyanobenzyl bromide is
accessible only in low yield by the radical bromination
of p-methylbenzonitrile and proved to be a very strong
lachrymator. Hence, another synthetic pathway was
finally employed using methyl 4-bromomethylbenzoate
which is much easier to handle. The dialkylation of 1
with methyl 4-bromomethylbenzoate gave derivative 5
in 69% yield. All our attempts at the direct transforma-
tion of ester 5 to the formyl derivative 4 have failed and
gave only inseparable mixtures of starting compound
and several products. On the other hand, an indirect
route via reduction of ester 5 to benzyl alcohol 6 and
subsequent oxidation8 to aldehyde 4 was accomplished
in an overall yield of 55%.
As already demonstrated, intramolecular McMurry
reactions4 of calix[4]arene derivatives bearing formyl
groups on the upper rim5,6 leads to systems with highly
strained structures. Thus, compound 2 possesses a
molecular cavity preorganised for possible complexa-
tion. On the other hand, the usage of this derivative as
The McMurry reaction was carried out9 by stirring 4
with a mixture of Zn and TiCl3·1.5DME complex.
Slightly better results (42% versus 35% yield) were
obtained using the Zn/TiCl4·2THF complex (commer-
cially available from Aldrich) in refluxing THF. This so
called ‘instant procedure’4 led exclusively to the product
of intramolecular coupling reaction 7, bridged by a
* Corresponding authors. Tel.: +420-224 354 280; fax: +420-224 354
288 (P.L.); tel.: +420-224 354 240; fax: +420-224 354 288 (I.S.);
e-mail: lhotakp@vscht.cz; stibori@vscht.cz
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00994-8

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P. Lhota´k et al. / Tetrahedron Letters 44 (2003) 4519–4522
cis-double bond in the cone conformation. Neither the
formation of possible intermolecular products nor the
corresponding trans isomer were observed.
prerequisite for efficient formation of CH-p interactions
in calix[4]arenes. It was demonstrated that bridging of
lower rim with two short diethylene glycol units12 or
fixation of C4v symmetry via metal coordination13 leads
to calix[4]arenes capable of forming inclusion com-
plexes with neutral guest molecules14,15 possessing
acidic CH2 or CH3 groups. During our study of the
solid-state behaviour of 7 we found that almost identi-
cal types of complexes could be obtained with several
other solvents, such as acetonitrile or acetone. In all
cases, the methyl group (possessing relatively acidic
The structures of the novel compounds were confirmed
1
by H NMR spectroscopy. All compounds 3–7 possess
typical features of distally disubstituted calix[4]arenes
being immobilised in the cone conformation. Thus, the
1H NMR (CDCl3) spectrum of compound 7 exhibited
two doublets at 4.39 and 3.39 ppm with geminal cou-
pling (J=13 Hz) corresponding to axial and equatorial
protons of Ar-CH2-Ar groups, respectively. The forma-
tion of a double bond in 7 was supported by the
disappearance of IR stretching for carbonyl groups
originally present in the starting compound 6 (1701
cm−1).
The structure of 7 was unequivocally proved by X-ray
crystallography.10 Suitable single crystals were grown
by slow evaporation of an ethyl acetate solution. The
molecule of calixarene 7 adopts a slightly pinched cone
conformation (aromatic part of the molecule exhibits
almost C4v symmetry, see Figure 1) the cavity of which
is held by intramolecular hydrogen bonds between two
phenolic OH functions and the neighbouring OCH2
groups. Obviously, the whole arrangement is reinforced
by the presence of the corresponding alkene bridge on
the lower rim. Interestingly, the cavity is filled by the
methyl group of ethyl acetate, held by the CH-p
interactions11 of hydrogen atoms with the aromatic
walls of the calixarene (Figs. 1 and 2). The methyl
group is situated almost exactly in the middle of the
cavity as indicated by the corresponding distances from
Figure 1. ORTEP drawing of complex 7 with ethyl acetate
(for clarity only aromatic part of the calixarene and the CH3
,
the centres of the aromatic rings (from 3.59 to 3.91 A).
It is known that suppression of the conformational
flexibility of the cone conformation is an important
,
group of acetate are depicted). All distances are in A.
Scheme 1. Synthesis of derivative 7 (Y=But). Reagents and conditions: (i) p-NC-C6H4CH2Br/K2CO3/acetone, reflux 1 week (58%);
(ii) DIBAL, chlorobenzene, 0°C (81%); (iii) p-MeOOC-C6H4CH2Br/K2CO3/acetone, 5 days reflux (69%); (iv) LiAlH4, rt (94%); (v)
PCC/CH2Cl2, 4 h, rt (59%); (vi) TiCl4·2THF/Zn/THF, reflux (42%).

P. Lhota´k et al. / Tetrahedron Letters 44 (2003) 4519–4522
4521
1
Figure 3. Partial H NMR spectrum (CDCl3, 300 MHz, 298
K): (a) free CH3CN; (b) the same sample after addition of 1
equiv. of 7.
Table 1. Complexation constants of compound 7 with
selected neutral guests (CDCl3, 298 K, 300 MHz)
Guest
K [M−1
]
CH3CN
19 2
4 2
CH3COCH3
CH3COOEt
NCCH2CN
ClCH2CN
0a
Figure 2. ORTEP drawing of complex 7 with ethyl acetate
(for clarity the CH3 group is shaded).
113 12
19 3
a No shifts upon addition of the guest molecule.
hydrogen atoms) is immersed deep in the cavity via
strong CH-p interactions. This indicates that
intramolecular bridging leads to a relatively rigid cav-
ity, which is suitably preorganised for the CH-p
interactions.
highest affinity (K=113 M−1) towards malondinitrile,
which is obviously the most acidic. On the other hand,
addition of ethyl acetate did not produce any measur-
able changes in the receptor molecule (<5 Hz).
To gain deeper insight into the complexation phe-
nomenon, the complexation ability of compound 7 was
also measured in solution (CDCl3) by standard 1H
NMR titrations with suitable neutral guest molecules.
As shown in Figure 3, the addition of 1 equiv. of 7 to
a solution of acetonitrile in CDCl3 leads to a dramatic
upfield shift (ca. 1 ppm). This strongly suggests that the
methyl group is shielded by magnetic anisotropy due to
the aromatic units being in a close proximity. This is
fully consistent with the assumption that the structure
of the complex in the solution is the same as that found
by X-ray crystallography in the solid state. Titration
curves were obtained using a constant calixarene con-
centration (1–3 mM) and increasing concentrations of
the appropriate guest to obtain different host/guest
ratios (0.1–20).16 All titration curves were constructed
from the CIS of the aromatic signals (D ppm:50 Hz)
and they reflect the 1:1 stoichiometry of binding. The
corresponding complexation constants are collected in
Table 1. It is evident that the preorganisation of the
molecule (alkene bridge together with hydrogen bonds)
enables efficient CH-p interactions in solution with
In conclusion, we have demonstrated that the
intramolecular bridging of calix[4]arenes via the
McMurry reaction leads to derivatives with a rigidified
cone conformation. The suppression of conformational
motion results in an enhanced ability to include neutral
guests inside a cavity suitably preorganised for the
binding via CH-p interactions. The design and synthesis
of other receptors of this type are currently under
investigation.
Acknowledgements
This research was partially supported by the Grant
Agency of the Czech Republic (GA 203/03/0926).
References
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4522
P. Lhota´k et al. / Tetrahedron Letters 44 (2003) 4519–4522
Kluwer Academic Publishers: Dordrecht, 2001; (b) Man-
(s, 18H, But), 1.04 (s, 18H, But). 1H NMR (CDCl3:
CD3OD=4:1 v/v, 300 MHz) l (ppm): 7.42 (d, 4H, J=8.2
Hz, H-arom), 6.88 (s, 4H, H-arom), 6.86 (s, 4H, H-
arom), 6.82 (s, 2H, -CHꢀCH-), 6.74 (d, 4H, J=8.2 Hz,
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1
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4H, Ar-H), 5.13 (s, 4H, -O-CH2-Ar), 4.26 (d, 4H, J=12.4
Hz, Ar-CH2-Ar ax.), 3.32 (d, 4H, J=12.4 Hz, Ar-CH2-Ar
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9. Preparation of compound 7: A mixture of 4 (0.525 g, 0.23
mmol), zinc dust (0.230 g, 1.84 mmol) and titanium(IV)
chloride·2THF complex (Aldrich, 0.596 g, 1.37 mmol)
was stirred at reflux in 50 ml of dry THF under argon.
The reaction mixture was refluxed for 20 h, then cooled
to rt and the solvent was removed under a reduced
pressure. The resulting solid was dissolved in CHCl3 and
filtered through the short column of silica gel to remove
all inorganic materials. The crude product was purified
using preparative TLC (20×20 cm) on silica gel (chloro-
form:petroleum ether=1:3) to yield 0.075 g (42%) of 7.
Mp: >360°C (CHCl3–MeOH, white crystals), 1H NMR
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4H, J=7.8 Hz, H-arom), 7.06 (brs, 8H, Ar-H), 6.99 (s,
2H, -CHꢀCH-), 6.91 (d, 4H, J=6.4 Hz, H-arom), 4.85 (s,
4H, -O-CH2-Ar), 4.39 (d, 4H, J=12.6 Hz, Ar-CH2-Ar
ax.), 3.39 (d, 4H, J=12.6 Hz, Ar-CH2-Ar eq.), 1.28
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